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| United States Patent |
5,738,869
|
|
Fischer
, et al.
|
April 14, 1998
|
Transdermal drug preparation
Abstract
The invention concerns a transdermal active-substance combination
containing phospholipid, alcohol and vitamin E.
| Inventors:
|
Fischer; Wilfried (Holzkirchen, DE);
Struengmann; Thomas (Holzkirchen, DE)
|
| Assignee:
|
Haxal AG (Holzkirchen, DE)
|
| Appl. No.:
|
535035 |
| Filed:
|
January 16, 1996 |
| PCT Filed:
|
April 22, 1994
|
| PCT NO:
|
PCT/EP94/01259
|
| 371 Date:
|
January 16, 1996
|
| 102(e) Date:
|
January 16, 1996
|
| PCT PUB.NO.:
|
WO94/25069 |
| PCT PUB. Date:
|
November 10, 1994 |
Foreign Application Priority Data
| Apr 23, 1993[DE] | 43 13 402.5 |
| Current U.S. Class: |
424/450; 424/45; 424/405 |
| Intern'l Class: |
A61K 009/127; A61K 009/06; A61K 009/10 |
| Field of Search: |
424/450,405,45
514/56
|
References Cited
U.S. Patent Documents
| 4239754 | Dec., 1980 | Sache et al. | 424/183.
|
| 4711906 | Dec., 1987 | von Stetten | 514/516.
|
| 4745105 | May., 1988 | Griffin et al. | 536/21.
|
| 4745107 | May., 1988 | Foley et al. | 514/56.
|
| 5482965 | Jan., 1996 | Rajadhyaksha | 514/452.
|
| 5498420 | Mar., 1996 | Edgar et al. | 424/450.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Sikha; Murthy
Attorney, Agent or Firm: Burgess, Ryan & Wayn
Claims
We claim:
1. Drug preparation containing phospholipid, which is a transdermal drug
preparation containing
water,
an aliphatic C.sub.1-6 -alcohol in the range from 1 to 50% (based on the
total weight of the preparation),
alpha-tocopherol or alpha-tocopherol ester and
a hormone, diclofenac Na or heparin Na as the drug.
2. Drug preparation according to claim 1, which contains .alpha.-tocopherol
or .alpha.-tocopherol ester in the range from 0.1 to 10%, based on the
total weight of the preparation.
3. Drug preparation according to claim 1 wherein the aliphatic alcohol is
an aliphatic C.sub.2 -C.sub.4 alcohol.
4. Drug preparation to claim 1 which contains phospholipid in the range
from 0.5 to 20%, based on the total weight of the preparation.
5. Drug preparation according to claim 1 which contains liposomes based on
the phospholipid.
6. Drug preparation according to claim 1 which is present as an ointment,
gel or spray.
7. Drug preparation according to claim 1, which contains .alpha.-tocopherol
or an .alpha.-tocopherol ester in the range from 0.5 to 7%, based on the
total weight of the preparation.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a transdermal drug combination containing
phospholipid, alcohol and vitamin E.
2. Prior Art
The transdermal administration of drugs, for example anti-inflammatory or
antithrombotic drugs, is appropriate in cases in which a high local
concentration of the drugs in the tissue under the intact skin is
necessary, while oral or parenteral systemic administration leads to
undesirable systemic side effects or it is not possible for this type of
administration to offer the local concentration necessary. Drugs such as
heparin sodium are in general employed topically in high concentrations
because of low skin permeability. The intestinal absorption of this drug
is negligible. Systemic effects are undesirable in the case of peripheral
injuries. Many topical drug formulations may sensitize, dry out or even
damage the skin where they are applied. Water-containing creams or
ointments, which are often intended to avoid some of these undesirable
side effects, must contain microbiological preservatives which for their
part often lead to skin sensitization. There is therefore a need for
safer, non-irritant absorption accelerators which additionally protect the
skin and which, for drugs having a low skin permeation ability, are
advantageous for increasing the drug concentration in the target tissue.
Diclofenac sodium is an example of a non-steroidal anti-inflammatory drug
(NSAID) which is employed extremely often, specifically in view of its
problem-free and well-established clinical efficacy. In order to decrease
the known local mucosal irritations after oral administration, topical
administration forms are desirable for chronic use in the case of regional
rheumatic symptoms. Metabolism in the first passage after oral
administration, which occurs in the liver and leads to partial
inactivation, can also be avoided by topical administration. In the
following exposition, diclofenac was selected as an example of drugs
having a low skin permeation ability.
The efficacy of topical diclofenac sodium preparations depends greatly on
the capacity of the preparation to allow the drug to penetrate the intact
skin. In particular, the horny layer represents a barrier for any drug
permeation of the skin and penetration into the underlying inflamed
tissue. Since the permeability of intact skin for diclofenac sodium is
low, various experiments have been undertaken to increase skin permeation
by use of various salts. IL-A-62 160 describes amine salts of diclofenac
for increased skin penetration. DE-A-3 336 047 (=GB-A-2 128 087) describes
a topical preparation based on an oil-in-water emulsion, which contains
the diethylammonium salt of diclofenac. This salt is more lipophilic than
the sodium salt and can permeate the skin at a higher rate. The use of
this salt, however, is not without risk. It is known that secondary amines
form highly carcinogenic nitrosamines. The preparation additionally
contains diethylamine as a neutralizing agent for acrylic acid, which acts
as a gel-forming agent for the gel preparation. Since secondary amines
have these potential side effects, the German authorities responsible for
registration (BGA) have recommended the replacement of these amines in
cosmetic and pharmaceutical preparations. EP-A-0 372 527 describes the use
of a hydroxyethylpyrrolidine salt of diclofenac having a higher water
solubility than in the case of the sodium salt. This salt was combined
with various absorption promoters, for example ethoxylated glycerides,
lanolin esters or lecithin. Only in combination with these new salts were
the absorption promoters able to accelerate the absorption to such an
extent as the diethylamine salt. For this, compare Clin. Tri. J., 26
(1989) 304-309 (Galzigna et al.: percutaneous absorption of diclofenac
after topical application, two different gel formulations). JP-A-02.049
722 describes the use of ammonia as a neutralizing agent for polyacrylic
acid gels containing diclofenac sodium. If, as a neutralizing agent, not
ammonia, but an alkylamine, for example monoethylamine, was taken, the
skin permeation in vitro fell from 44.8 to 1.7%. EP-A-0 498 011 describes
rubidium or caesium salts of diclofenac having a higher skin permeation in
vitro than in the case of the sodium salt. The use of these salts,
however, is critical, since both ions display their own pharmacological
effects. Antidepressant effects thus occur, and, in particular, caesium
increases the cerebral concentrations of serotonin and tryptophan. Its
very long elimination half-life (50 to 100 days) can lead to accumulation
in the body after chronic administration. Rubidium likewise has a long
elimination half-life (40 days) and leads to a long-term accumulation. In
some cases, it can increase central nervous activity and aggressiveness.
EP-A-0 245 126 describes the calcium salt of diclofenac in combination
with toxicologically hazardous absorption promoters, such as DMSO and
azones. Besides the use of novel salts of diclofenac, various preparations
containing synthetic absorption promoters have been developed. JP-A-01.013
020 thus describes diclofenac sodium emulsions, which contain dialkyl
carboxylates and fatty acids, for topical use. A protective agent is
additionally added in order to reduce microbiological contamination.
According to WO-A-88/04 938, heterocyclic penetration accelerators, such
as imidazolines or oxazolines, are employed for topical pharmaceuticals
comprising diclofenac. The disadvantages of such accelerators, however,
are their possible skin irritation and sensitizations. U.S. Pat. No.
4,670,254 describes diclofenac sodium gels which contain a high amount of
ethanol and propylene glycol. Ethanol is a known absorption promoter for
various drugs. Ethanol and propylene glycol are solvents for lipids and
have the disadvantage that they dry out the skin. JP-A-60.146 823 uses
nicotinates as absorption accelerators. As drugs, they lead to increased
circulation and increased blood flow and thus accelerate transport from
the administration site. They lead to hot sensations and disturbing side
effects. EP-A-0 147 476 uses glycols and salicylates or peppermint oil or
menthol as absorption accelerators. These substances, however, can cause
skin irritations, and peppermint oil or menthol can lead to burning or to
sensitization of the skin.
It is also known that phospholipids can increase the moisture content of
the skin and the permeation of drugs through the skin. The literature
reports for diclofenac sodium, however, are contradictory. According to
Chem. Pharm. Bull., 35 (1987) 3807-3812 (Nishihata et al.) the permeation
in vitro through rat skin increases if diclofenac is employed in an
aqueous gel containing hydrogenated soya bean phospholipids (30%
phosphatidylcholine and 70% phosphatidylethanolamine; iodine value about
6%). The amount permeated after 7 h was 5 times higher in the case of the
gel containing 0.5% hydrogenated phospholipids than in solution without
phospholipids. The drug concentration was 1.25% in each experiment. On the
other hand, according to 2nd Liposome Research Days, N. L. Leiden, June
1992, page 5 (Enghausen & Muller-Goymann), phospholipids should show no
accelerating effect in vitro even when an isolated stratum corneum was
pretreated with phospholipids. This last-mentioned result agrees with
observations of the inventors (Comparison Example 1).
SUMMARY OF THE INVENTION
The invention is based on the object of improving the permeation ability of
transdermal drug preparations containing phospholipids.
According to the invention, it was surprisingly found that in the case of
such transdermal drug preparations the permeation ability can be
advantageously improved by the addition of vitamin E (.alpha.-tocopherol)
or by addition of vitamin E derivatives. Embodiments of the invention are
covered by the subject-matter of the patent claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The combination of phospholipids with tocopherol or tocopherol derivatives
and short-chain aliphatic alcohols leads to an unexpectedly high skin
permeation in the case of drugs having a low permeation ability. Examples
of such drugs are non-steroidal anti-inflammatory, antithrombotic,
analgesic, anaesthetic, antibiotic, hormonal and antiallergic drugs. The
drug preparations can be topical solutions, foes, sprays, gels, pastes,
ointments, emulsions and liposomal dispersions. Since in the case of low
alcohol concentrations an antimicrobial activity is produced, the use of
additional preservatives is not necessary. Since, according to the
invention, tocopherol or a tocopherol derivative is provided, further
antioxidants are not necessary.
Drug preparations of the composition according to the invention are safe,
non-toxic, well tolerable and have a skin protectant action which can be
attributed to tocopherol or tocopherol derivatives. Reference may be made
to the cosmetic preparations which are used widely and which are intended
to prevent exogenous skin damage, for example due to UV irradiation. The
preparations according to the invention are superior in comparison with
known topical drug preparations, since absorption promoters or, under
certain circumstances, not unhazardous salts are avoided, which can lead
to skin irritation or even to skin damage.
It emerges from the following experimental data that the addition of
vitamin E (.alpha.-tocopherol) or one of its derivatives surprisingly
raises the permeation drastically above the value applying for a
diethylammonium diclofenac gel. Values of up to approximately 4000 .mu.g
of drug/2.5 cm.sup.2 could thus be determined (Table 1).
The invention is illustrated in greater detail below with the aid of
examples and figures:
FIG. 1 shows a skin permeation profile in vitro of a diclofenac sodium gel
of the prior art;
FIG. 2 shows a skin permeation profile in vitro of a diclofenac sodium gel
according to the invention; and
FIG. 3 shows plasma levels as a function of time for a diclofenac Na gel
according to the invention and according to the prior art, respectively.
COMPARISON EXAMPLE 1
(Diethylammonium diclofenac)
Skin permeation studies were carried out, dissected skin of nude mice being
used in modified Franz cells. The permeation area was 2.5 cm.sup.2. The
acceptor medium was physiological saline solution at 34.degree. C. A
typical skin permeation profile is shown in FIG. 1. A commercially
available emulgel (Voltaren) was used as a reference. It contains the
diethylammonium salt of diclofenac. All amounts which permeated were
expressed on the basis of diclofenac sodium. From this experiment it was
possible to calculate an approximate flow rate of J=36 .mu.g of
drug/cm.sup.2 /h. The diethylammonium diclofenac gel had a permeation of
approximately 2000 .mu.g of drug/2.5 cm.sup.2 /24 h.
COMPARISON EXAMPLE 2
(Diclofenac sodium)
The skin permeation of saturated aqueous solutions and 1 per cent solutions
was measured for a mixture of isopropanol and propylene glycol. The
results can be seen in Table 1 below. The amount of drug which permeated
through the skin in vitro in 24 hours in the case of a saturated and
aqueous solution was thus 984 .mu.g of drug/2.5 cm.sup.2. This solution
had maximum thermodynamic activity. A 1 per cent aqueous solution
containing isopropyl alcohol and propylene glycol had a much lower
permeation of 135 .mu.g of drug/2.5 cm.sup.2. The addition of 2% purified
natural soya bean lecithin (about 80% phosphatidylcholine, 2%
lysophosphatidylcholine, 4% phosphatidic acid and 1%
monophosphatidylinositol) increased the permeation rate by a factor of
approximately 5 to 750 .mu.g of drug/2.5 cm.sup.2, which approximately
corresponded to the value of a saturated solution without absorption
promoter. Phospholipids without addition of the alcohols led to a lower
value of 230 .mu.g of drug/2.5 cm.sup.2.
TABLE 1
______________________________________
Amounts of diclofenac sodium (.mu.g/2.5 cm.sup.2) which
diffused in 24 h in various solvents
saturated
1 per cent
1% in 1% in 1% in
aqueous
aqueous IPA/PG water con-
IPA/PG water +
solution
solution water taining 2% PL
2% PL
______________________________________
984 398 150 230 750
______________________________________
IPA: Isopropyl alcohol
PG: Propylene glycol
PL: Phospholipid (as indicated above)
Since the solubility in water is approximately 1.9%, the values for skin
permeation for solutions in water agree with the concentration
differences. The 1:1 mixture of isopropanol (IPA) and propylene glycol
(PG) with 6% water appears to decrease the drug permeation. The use of the
phospholipid alone without addition of alcohols is also insufficient to
achieve the permeation of a saturated solution in water.
EXAMPLE 1
The addition of .alpha.-tocopherol or .alpha.-tocopherol acetate to the
solution of diclofenac sodium as the drug, PL and alcohols leads to an
unexpectedly high skin permeation (Table 2). The drug solutions were
gelled with polyacrylic acid and triethanolamine in order to form a
readily administrable preparation. The skin permeation is only slightly
affected by this modification (Table 2).
TABLE 2
______________________________________
Amounts of diclofenac sodium (.mu.g/2.5 cm.sup.2) which
diffused in 24 h after addition of PL, .alpha.-tocopherol or
.alpha.-tocopherol acetate and IPA.
1% Diclofenac NA solution
1% Diclofenac NA gel
______________________________________
3711 3350
______________________________________
Both preparations contained identical amounts of PL and IPA. The solution
contained 5% d,l-.alpha.-tocopherol acetate and the gel 1%
d-.alpha.-tocopherol. The gel additionally contained 1.5% polyacrylic acid
and a sufficient amount of triethanolamine for gelling the polymer. In
order to increase the spreading of the gel, a mixture of synthetic oil
components was incorporated into the gel. The skin permeation data in
vitro of a complete diclofenac Na gel preparation can be seen from FIG. 2.
The flow rate calculated from these data is J=56 .mu.g of drug/cm.sup.2 /h.
It is 1.55 times higher than that of a standard preparation.
Use Example 1
(Diclofenac Na solution)
The following solution can be used as a topical antirheumatic spray:
______________________________________
Diclofenac Na 1%
Phospholipon 80 2%
d,1-.alpha.-Tocopherol acetate
5%
Isopropanol 20%
Water 72%
______________________________________
Use Example 2
(Heparin Na gel)
The following gel can be used as a topical antithrombotic preparation:
______________________________________
Heparin Na 0.5%
Phospholipon 80 2%
d-.alpha.-Tocopherol 1%
Polyacrylic acid 1.5%
Triethanolamine 2.5%
Isopropanol 20%
Water 72.5%
______________________________________
Use Example 3
(Diclofenac Na gel)
The following gel can be dispersed on the skin very readily. It can be
applied to inflamed areas of the body.
______________________________________
Heparin Na 1%
Phospholipon 80 2%
d-.alpha.-Tocopherol 1%
Polyacrylic acid 1.5%
Triethanolamine 2.5%
Decyl oleate 5%
Isopropanol 20%
Water 67%
______________________________________
Use Example 4 and Comparison Use Example 1
(Diclofenac Na gels)
Use Example 3 was repeated (Use Example 4). 7.5 g of the 1 per cent
diclofenac Na gel were applied in each case to the backs of 12 subjects
and washed off after an application period of 6 hours.
For comparison, 7.5 g of a commercially available 1 per cent diclofenac Na
gel (Voltaren) were in each case applied to the backs of 12 subjects, the
gels again being washed off after an application period of 6 hours.
The average values of the plasma levels are shown graphically in FIG. 3.
FIG. 3 shows that in Use Example 4 the plasma level was still increasing
when the applications were discontinued. In contrast, in Comparison Use
Example 1 the plasma level fell even before discontinuing the
applications, at an application period of about 5 hours. This fall must be
attributed to the fact that the comparison gel does not contain any
phospholipid and/or .alpha.-tocopherol.
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